It is unclear how vertical sleeve gastrectomy (VSG) leads to the rapid clinical amelioration of type 2diabetes. This knowledge gap reflects an incomplete understanding of the systems regulating glucose metabolism and prevents the potential development of novel pharmacological therapies for diabetes. The long-term goal of this research is to advance our knowledge of CNS regulation of glucose and energy homeostasis after bariatric surgery. The objective of this proposal is to elucidate how VSG leads to rapid glycemic improvement. We established a model of VSG utilizing mice with obesity and impaired glucose regulation. Our investigations on diet-induced obesity (DIO) mice and leptin-deficient (ob-ob) mice led us to find that DIO mice have a similar glycemic response to humans with type 2 diabetes that undergo VSG. DIO mice after VSG experience a rapid and marked reduction in glycemic levels that is weight loss-independent and unrelated to acute surgical effects, such as increased catabolism and decreased food intake. In spite of becoming nearly hypoglycemic in the first few days after VSG, DIO mice do not respond to this with increased glucagon secretion and hepatic glucose production. On the other hand, ob-ob mice's glycemic level after VSG is similar to the control groups that undergo sham operation. Based on preliminary data gathered by the applicant, the central hypothesis is that VSG alters gastric neural input to the brain, leading to a transient, leptin-dependent or facilitated inhibition of central glucose counter-regulatory mechanisms that protect against hypoglycemia by increasing peripheral blood glucose. The rationale for the proposed research is that it may pave the way for the development of novel therapies for type 2 diabetes based on the effects of VSG on glucose homeostasis. The central hypothesis will be tested by pursuing the following three specific aims: 1) Establish the contribution of gastric denervation to the effects of VSG on glucose metabolism; 2) Determine the contribution of glucose counter- regulation to the early glycemic effects of VSG; and 3) Define the role of leptin in the acute glycemic lowering after VSG. Under the first aim, validated techniques will be used to determine if gastric denervation contributes to the glycemic effects of VSG and whether this surgical procedure alters neural input to specific glucose regulating centers in the brain. For the second aim, we will induce hypoglycemia in mice that undergo VSG and evaluate their glucose counter-regulatory response. We will also generate a transgenic mouse with permanently activated glucose counter-regulation and assess the efficacy of VSG on that model. Finally, under aim 3, we will define if leptin's central (as opposed to peripheral) effects are essential for the glycemic improvement after VSG by performing the surgery on mice with specific deletion of the leptin receptor either in the brain or in the liver. The approach is innovative because it shifts the focus from long-term to the early glycemic effects of VSG. The significance of the proposed research is that it may advance our knowledge of how the gastrointestinal tract and the brain exchange information in order to regulate glucose metabolism.